Opinion: Neoadjuvant Immunotherapy May Improve Outcomes in Sarcoma

Amanda Brink, DNP, APRN, FNP-BC, AOCNP

Treating patients with sarcoma presents a challenge for oncology nurses and providers due to the rarity of this cancer type and the variety of subtypes, each with its own distinct biology and behavior. Sarcoma, which accounts for less than 1% of cancer diagnoses in adults and 15-20% of childhood cancers,¹ is made up of approximately 100 different subtypes.²

Dedifferentiated liposarcoma (DDLPS), characterized by its aggressive nature and high-grade features, constitutes 40-45% of all liposarcomas, a subset that represents 15-20% of all soft tissue sarcomas. DDLPS typically occurs in older adults between the ages of 50 and 70. Most patients are diagnosed with DDLPS as a new primary tumor, while some occur in the context of a previously diagnosed well-differentiated liposarcoma that has transformed into DDLPS. DDLPS frequently occurs in the retroperitoneum and is diagnosed as a large, painless mass. However, it may also originate in other areas of the body, including the extremities, and can metastasize to distant sites such as the lungs, liver, and bones, among others.³

The primary treatment option for localized DDLPS is surgery. Neoadjuvant and adjuvant systemic therapy may be utilized, especially in cases where the primary tumor is considered borderline resectable surgically or located near other anatomically critical structures, such as major blood vessels. Such therapy may help reduce the risk of recurrence after surgery.

Undifferentiated pleomorphic sarcoma (UPS) is another type of soft tissue sarcoma commonly located in the trunk of the body and the extremities. Like DDLPS, it is typically diagnosed in older adults and presents as a painless mass. Surgery is the primary treatment option for localized disease, with adjuvant radiation therapy and neoadjuvant chemotherapy playing a role in some patients.⁴

Neoadjuvant Immunotherapy in DDLPS and UPS

Recent evidence suggests that immunotherapy agents have activity in metastatic DDLPS and UPS. Building on this evidence, Roland et al. conducted a randomized, non-comparative phase 2 study of neoadjuvant immune checkpoint inhibitors in resectable retroperitoneal DDLPS and extremity/truncal UPS (NCT03307616).⁵ Patients were randomized 1:1 to receive neoadjuvant single agent nivolumab (Opdivo) or combination nivolumab and ipilimumab (Yervoy). Patients with UPS were also treated with radiation therapy. All patients underwent surgical resection after completing neoadjuvant therapy.⁶

A total of 27 patients were eligible and treated in the study, 17 with DDLPS and 10 with UPS. Among them, 8 patients with DDLPS received single agent nivolumab, while 9 received a combination of nivolumab and ipilimumab. Six patients with UPS were treated with nivolumab in conjunction with radiation, and 4 were administered a combination of nivolumab, ipilimumab, and radiation therapy. Seventy-four percent of patients (n= 19) completed all doses of neoadjuvant immunotherapy. Patients in the single agent nivolumab arms were more likely to complete the entire therapy course compared to those in the combination nivolumab and ipilimumab arms.⁶

The adverse reactions observed were in line with the established safety profiles of both nivolumab and the nivolumab-ipilimumab combination. Among the 27 patients, 7 (25.9%) experienced grade 3 or higher treatment-related adverse events.⁶

In this study, the pathologic response was evaluated based on the percent of hyalinization at the time of surgical resection. Percent hyalinization refers to the extent of hyalinized or fibrotic tissue present in a tumor specimen after treatment. Hyalinization occurs when tissue undergoes a process of fibrosis, leading to the formation of a dense, homogenous, glassy material known as hyaline. In the context of a pathologic response assessment, a higher percentage of hyalinization typically indicates a more favorable response to treatment.⁷

The median percent of hyalinization was 8.8% (IQR 2.5%-20%) in patients with DDLPS and 89% (IQR 40%-95%) in patients with UPS, with similar findings observed between the nivolumab (DDLPS: 15%, UPS: 90%) and nivolumab/ipilimumab (DDLPS: 7.5%, UPS: 61.5%) groups. The median residual viable tumor was 77.5% (IQR 62.5%–92.5%) in DDLPS and 3.5% (IQR 0%–15%) in UPS, with no significant differences between the groups. For comparison, historical data from the institution where the study was conducted indicated a median hyalinization of 17.5% in patients with extremity/truncal UPS who received preoperative radiation therapy alone before surgery.⁶

The patients were monitored for relapse and survival following surgery. Thirteen patients experienced relapse (n = 13 out of 25, 52%; DDLPS: n = 11 out of 16, 69%; UPS: n = 2 out of 9, 22%) after surgery. Relapse-free survival (RFS) at 24 months was 38% in DDLPS (IQR 15%–60%; single agent nivolumab 25%, IQR 4%–56%; nivolumab/ipilimumab 50%, IQR 15%–77%) and 78% in UPS (IQR 36%–94%; single agent nivolumab 60%, IQR 13%–88%; nivolumab/ipilimumab 100%). Overall survival (OS) at 24 months was 82% in DDLPS (IQR 55%–94%; single agent nivolumab 88%, IQR 39%–98%; nivolumab/ipilimumab 78%, IQR 36%–94%) and 90% in UPS (IQR 47%–99%; single agent nivolumab 83%, IQR 27%–97%; nivolumab/ipilimumab 100%).⁶

Despite the study authors' observation that the pathological response to immunotherapy was less robust in DDLPS compared to UPS, the 1-year relapse-free survival rate remained high. This observation is noteworthy due to the presence of unfavorable prognostic factors among patients with DDLPS in this study, including high grade, recurrent DDLPS, and multifocal disease.⁶

Nursing Considerations

As is the case with many patients with cancer, surgical resection offers the best chance for cure in patients with DDLPS and UPS. Therefore, any avenue that can be explored to improve patients' surgical candidacy and prevent relapse after surgery should be pursued.

Oncology nurses should encourage patients undergoing immunotherapy to promptly report any side effects. By doing so, side effects can be managed when they are more likely to be of lower grade. This proactive approach enhances the likelihood of patients completing all planned treatments, thereby potentially leading to more favorable overall outcomes.

Oncology nurses can also facilitate clinical trial participation for patients with sarcoma, as recruiting for clinical trials in sarcoma can be challenging due to the rarity of this disease. Educating patients about the benefits of trial participation, especially in the neoadjuvant setting, can significantly impact enrollment rates.

References

1. 2022 estimates for sarcomas in the United States. Sarcoma Foundation of America. Accessed March 16, 2024. https://www.curesarcoma.org/wp-content/uploads/Sarcoma-Statistics-2022.pdf
2. Full list of sarcoma subtypes. Sarcoma UK. January 11, 2024. Accessed March 16, 2024. https://sarcoma.org.uk/about-sarcoma/what-is-sarcoma/types-of-sarcoma/full-list-of-sarcoma-subtypes/
3. Gahvari Z, Parkes A. Dedifferentiated Liposarcoma: Systemic Therapy Options. Curr Treat Options Oncol. 2020;21(2):15. Published 2020 Feb 5. doi:10.1007/s11864-020-0705-7
4. Crago AM, Cardona K, Koseła-Paterczyk H, Rutkowski P. Management of Myxofibrosarcoma and Undifferentiated Pleomorphic Sarcoma. Surg Oncol Clin N Am. 2022;31(3):419-430. doi:10.1016/j.soc.2022.03.006
5. Nivolumab with and without Ipilimumab and Radiation Therapy in Treating Patients with Recurrent or Resectable Undifferentiated Pleomorphic Sarcoma or Dedifferentiated Liposarcoma Before Surgery. Clinicaltrials.gov. Accessed March 17, 2024. https://clinicaltrials.gov/study/NCT03307616
6. Roland CL, Nassif Haddad EF, Keung EZ, et al. A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma. Nat Cancer. Published online February 13, 2024. doi:10.1038/s43018-024-00726-z
7. Augustine D, Rao RS, Patil S. Hyalinization as a histomorphological risk predictor in oral pathological lesions. J Oral Biol Craniofac Res. 2021;11(3):415-422. doi:10.1016/j.jobcr.2021.05.002